Incorporating Early Assessments of Cardiovascular and CNS Safety into Early Clinical Studies Bruce H Morimoto, PhD Dec 8, 2015

Objectives of Early Clinical Research

1. Establish safety Understanding the maximum tolerated dose or maximum

feasible dose in human Translation of nonclinical to clinical observations Unexpected safety observations

2. Understand pharmacokinetics (dose-exposure) 3. Explore potential for efficacy Clinical outcome measures Biomarkers (target engagement, mechanism-of-action)

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CNS Safety Assessment

Why Monitor CNS Safety?

Early decision-making Critical for tolerability profile and appropriateness of

patient populations Product differentiation

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CNS Side-effects from Non-CNS Drugs

Examples: Cardiovascular

Beta-blockers for hypertension can result in insomnia, depression, nightmares

ACE inhibitors: dizziness, drowsiness, light headedness Respiratory

Anti-histamines. non-sedating do not cross the BBB Anti-viral

Non-nucleoside reverse transcriptase inhibitors, like efavirenz (Sustiva®), rilpivirine (Edurant®), can result in mood changes, anxiety, dizziness, sleep disturbance (insomnia, nightmares), and even psychosis

Immune modulators Metabolic disease

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Unwanted CNS Activity

On-target, wrong tissue Anti-histamines Sedating: can cross BBB Non-sedating: can’t cross BBB

Off-target Neurotransmitter receptors (dopamine, serotonin, GABA and

acetylcholine) Efanirenz (NNRTI) interacts with 5-HT2A/C receptors, serotonin &

dopamine reuptake, monoamine transporter, and GABAA receptors

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Polypharmacy. Potential for Synergism

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From Cambridge Cognition©

Alone the drugs had a minimal effect, but in combination the negative effect on reaction times was equivalent to having a blood-alcohol level of 0.1%.

Reaction Time

Spatial Working Memory

Rapid Visual Information Processing

Cambridge Cognition (Computerized Tests)

Paired Associates Learning

From Cambridge Cognition©

Clinical Trial Information System (CTIS) Profile

Reaction Time (RTI)

Assay for mental response speeds

as well as movement times

and accuracy

Paired Associates Learning

(PAL)

A visual associative memory and new learning task to

accurately assess episodic memory

Spatial Working Memory (SWM)

Requires retention and manipulation of

visuo-spatial information.

Measures working memory and

executive function

From Cambridge Cognition©

Validity and Sensitivity Sensitivity to

Cognitive Impairment

Sensitivity to Cognitive

Enhancement Validity

Spatial Working Memory

(SWM)

Tyrosine depletion in healthy

subjects (d=0.42) (Harmer et al., 2001).

Methylphenidate in healthy

subjects (d=1.51) (Elliot et al., 1997).

Owen et al., 1990; Manes et al., 2002; Owen et al., 1996

Paired Associates

Learning (PAL)

Scopolamine in healthy

Subjects (d=1.12) (Rusted & Warburton, 1988). Rosiglitazone (no placebo) in

diabetes (d=0.69) (Ryan et al., 2006).

Phenserine in patients

with Alzheimer’s disease (d=0.46)

(Greig et al., 2005).

Owen et al., 2002;

Swainson et al., 2001; de Rover et al., 2011

Reaction time (RTI)

Clonidine in healthy subjects

(d=1.52) (Jakala et al., 1999).

Caffeine in healthy volunteers (d=0.44)

(Attwood et al.,2007).

Robbins, 2002

Published data show that drugs can improve or impair performance in these tests

From Cambridge Cognition©

Sensitivity of Outcome Measure

Effect size’s greater than 0.8 are considered to be “large” and would be expected to be clinically significant, and require serious evaluation by the clinical study team.

Large effect size**

**Cohen (1988), Kraemer and Kupfer (2006)

From Cambridge Cognition©

Key Properties of CTIS Profile

Summary Three tests included in battery covering a wide range of cognitive domains Takes a little over 20 minutes to complete Can be used repeatedly (especially when test sessions are well spaced

out) Change with age is well documented Test performance correlates with real life cognitive performance Tests performance can be improved or impaired by drug treatment Can detect clinical significant sized effects as well as sensitive to more

subtle changes Effects on peripheral mechanisms have been shown to influence test

performance

From Cambridge Cognition©

Cardiovascular Assessments

The Evolution of Cardiac Safety Testing

1997 2001 2003 2005

Points to Consider

1999

Joint Health Canada/FDA

Concept Paper

Health Canada Concept Paper

FDA & CHMP Adopt E14

Health Canada Adopts E14

ICH issues S7B and E14 Guidance

2007 2009 2011

E14 Q&A

IRT Started

2013 2015

E14 Q&A revised

?? preDiCT Project begins

ARITMO Project begins

Cases of Torsades de Pointes

Annual number of spontaneous reports of Torsade de Pointes received by the US FDA Adverse Event Reporting System, Stockbridge et al. Drug Safety 2013;36:167-182

ICH S7A ICH E14 & S7B

Preclinical testing

Current Regulatory Guidance (Nonclinical)

ICH S7A (Safety Pharmacology) Cardiovascular system

Core battery: blood pressure, heart rate, ECG Follow-up: cardiac output, ventricular contractility, vascular

resistance

ICH S7B (QT prolongation) Ikr (hERG) assay In vivo (telemetry) QT assessment Chemical/pharmacological class Integrative risk assessment

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Current Clinical Cardiac Safety Guidance

ICH E14 (QT/QTc prolongation and proarrhythmic potential) Specifies Thorough QT/QTc study

Threshold for regulatory concern: 5 ms change in QTc Typically done in healthy subjects Positive control (often moxifloxacin)

E14 Questions and Answers (2008) Provided clarifications

Positive control to establish assay sensitivity (lower bound of one-sided 95% CI must be above 0 ms)

Who should read ECGs (must be blinded, cardiologist over-read acceptable)

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Current Debate

Does the TQT truly predict a compound’s proarrhythmia potential?

There have been tremendous advancements in both pre-clinical and early clinical monitoring of arrhythmia potential since 2005. How does this: Change proarrhythmia evaluation pre-clinically and/or clinically? Change the need for a TQT?

What has been the impact of ICH E14 and S7B on drug development? Is it worth the cost?

What does a positive TQT really mean?

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Relationship of QT Prolongation and Human Risk

Cardiac Arrest

Ventricular

Fibrillation

Ventricular Arrhythmia Torsades de Pointes

QT Prolongation Early After Deploarizations

Cardiac Action Potential: Delayed Repolarization

From: Morimoto and Fox (2011) In: Principles and Practice of Pharmaceutical Medicine (Edwards, Fox and Stonier, ed.) 3rd ed. Wiley-Blackwell

Is there an Alternative to Thorough QT Studies?

Increase Nonclinical Testing

Comprehensive In vitro Proarrhythmia Assay (CiPA) Initiative Ion channels

Perform comprehensive tests (hERG plus 3 to 6 additional cardiac channels)

Stem cell-derived human cardiomyocytes In silico modeling

Result: update ICH S7B

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Early Clinical Cardiac Safety Evaluation

Proposal: Include intense ECG monitoring to early Single Ascending

Dose (SAD) and Multi Ascending Dose (MAD) studies Pool data from different dose levels to evaluate concentration

response relationship Typically during SAD and MAD studies the highest doses are

given allowing for better concentration response modeling

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Early Clinical Cardiac Safety Testing

Consortium for Innovation and Quality in Pharmaceutical Development/Cardiac Safety Research Consortium (IQ/CSRC) Look at six marketed drugs, 5 positive QT signal and 1 negative control Two doses: 10-12 ms and 15-20 ms

Ondansetron, dofetilide, quinine, dolasetron, moxifloxacin Levocetirizine (negative control)

SAD-like study QT assessment criteria: The upper bound of the two-sided 90%

confidence interval (CI) of the projected placebo-corrected delta QTcF is above 10 ms at the observed peak plasma level of the drug

Sensitivity and specificity of measuring QT prolongation Concern over potential false negatives (regulators) and false positives

(sponsor)

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IQ-CSRC Study

3 period, randomized, placebo-controlled study Incomplete block design used

Each study drug administered to 9 subjects and placebo to 6 (total n=20)

Continuous 12-lead ECGs with replicate ECGs extracted Exposure response analysis performed

Evaluate relationship between plasma concentration and placebo corrected, change-from-baseline QTc (∆∆QTc)

“QT positive” if the UB of the 2-sided 90% CI of the predicted placebo-corrected ∆QTcF is above 10 ms at the observed geometric mean Cmax of the lower dose of the studied drugs

Darpo et al. (2014) Ann Noninvasive Electrocardiol 19, 70-81 Darpo et al. (2015) Clin Pharmacol Ther 97, 326-335.

IQ-CSRC: Pharmacokinetics and QT Data

25 Darpo et al. (2015) Clin Pharmacol Ther 97, 326-335

IQ-CSRC Study: Exposure-response Results

26 Darpo et al. (2015) Clin Pharmacol Ther 97, 326-335

Implications of IQ-CSRC Study

No positive control in SAD Reassurance against false negatives Risk is small when exposure-response analysis is applied and

offset by wide range of plasma concentrations Quality test metrics

HR stability within time points Reproducible QT/RR curvature Within and between subject variability of QT Time course of QT adaptation to changes in HR

Study was SAD-like, not exactly like a dose-escalation study Group sizes were larger than “typical” SAD

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Future Directions

Need further replication of the IQ-CSRC study Pharmacokinetics will drive study design Pronounced accumulation on multi-dosing? Sufficiently high plasma concentration of parent and

metabolites? Could TQT waiver be obtained?

28 From: Dreamstime.com

References

Darpo et al. (2015) Implications of the IQ-CSRC prospective study: time to revise ICH E14. Drug Saf 38, 773-780

Darpo et al. (2015) Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase. Clin Pharmacol Ther 97, 326-335

Darpo et al. (2014) The IQ-CSRC prospective clinical Phase 1 study: “Can early QT assessment using exposure-response analysis replace the thorough QT study?” Ann Noninvasive Electrocardiol 19, 70-81

Cavero & Holzgrefe (2015) CiPA: ongoing testing, future qualification procedures, and pending issues. J Pharmcol Toxicol Methods 76, 27-37

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Questions? bruce.morimoto@celerion.com